Development of the beta-lactam structure as a scaffold for biologically active compounds

Abstract

Tamoxifen is a selective estrogen receptor modulator (SERM) with a triarylethylene structure which acts as an estrogen antagonist in the breast. This drug is used extensively as an endocrine treatment for breast cancer, however, due to its flexible structure it can also act as an agonist in endometrial tissue resulting in unwanted side effects including endometrial cancer. Many modified SERMs have been developed based on non-isomerisable scaffold structures. In this thesis, the design and synthesis of structurally optimised conformationally constrained Selective Estrogen Receptor Modulators is described. These products contain the β-lactam structure and show potential therapeutic application as antiestrogens. Combretastatin A-4 is a small biologically active molecule which is currently in clinical trials for the treatment of solid tumors. It, too, contains an isomerisable double bond and CA-4 is only active in its trans configuration. The β-lactam ring is used to form a selection of structurally restricted analogues of CA-4 which will contain the desired configuration for activity.